HIV causes neurologic disorders (NeuroAIDS) ranging from minor cognitive and motor disorders to HIV- associated dementia (HAD). A better understanding of the underlying mechanisms of NeuroAIDS is needed because it would suggest therapeutic approaches for NeuroAIDS. Towards this goal, our strategy is to define the interplay between endogenous neuroprotective mechanisms and HIV in brain cells. Wnt/-catenin activity is a pro-survival signal in neurons and astrocytes. Wnt/-catenin regulates ~500 genes involved in diverse cell functions such as cell proliferation and survival throughout the body, including the CNS. Mounting evidence links decreased levels of -catenin and neurodegeneration. Yet, the role of Wnt/-catenin activity in NeuroAIDS is unclear. We reported an inverse relationship between Wnt/-catenin activity and HIV replication. Specifically, we demonstrated that active Wnt/-catenin inhibits whereas inactive Wnt/-catenin induces HIV replication. Further, IFN, a proinflammatory cytokine associated with HAD severity, and Tat, an HIV-encoded regulatory protein, both diminished Wnt/-catenin signaling in astrocytes. We propose that (i) Wnt/-catenin signaling (Wnt) is a key regulator of HIV replication and homeostasis in the brain, and (ii) Wnt down-regulation (mediated by Tat or IFN) promotes astrocyte and neuronal apoptosis, which contributes to the pathogenesis of HIV disease in the CNS. In Aim 1, using astrocytes (which have high endogenous Wnt/-catenin expression) we will define the mechanism by which Wnt/-catenin regulates HIV replication. In Aim 2, using astrocytes, microglia, and monocyte-derived macrophages, we will determine the role of host (IFN) and viral (Tat) factors in modulating Wnt/-catenin signaling and HIV replication. In Aim 3, using primary human fetal mixed glial/neuronal brain cell cultures, we will determine the consequences of modulation of brain Wnt activity on the survival of astrocytes and neurons. Collectively, these studies will lead to a better understanding of the role of brain Wnt/-catenin activity on HIV replication and glial/neuronal survival. These studies could also expedite the development of activators of -catenin signaling that can penetrate the CNS, suppress HIV replication, and enhance survival of astrocytes and neurons.